Table 5.
Performances of selected biomarkers of responses to therapy in LN.
| Biomarker | Sample | Main Findings | References |
|---|---|---|---|
| Autoantibodies | |||
| Anti-dsDNA (-) (disappearance at month 6) | Serum/Plasma | Sens.: 70%; spec.: 56%; PPV: 67%; NPV: 59% to predict a CRR by month 12 | Mejia-Vilet et al., 2020 [101] |
| Complement | |||
| C3 (↑) (normalization or 25% increase at month 6) |
Serum/Plasma | Sens.: 65–70%; spec.: 67–72%; PPV: 73–75%; NPV: 62–63% to predict CRR by month 12 | Mejia-Vilet et al., 2020 [101] |
| Kidney disease-related markers | |||
| Proteinuria (↓) (baseline levels 0.1–0.87 g/24 h) |
Urine | Low levels are predictive of CRR at 6 months (OR = 4.3) after immunosuppressive therapy | Ichinose et al., 2018 [137] |
| uPCR (↓) (<1.5 g/g at month 6) |
Urine | Sens.: 86%; spec.: 81%; PPV: 81%; NPV: 86% to predict CRR by month 12 | Mejia-Vilet et al., 2020 [101] |
| Cytokines/chemokines | |||
| APRIL (↑) (baseline levels >4 ng/mL) |
Serum/Plasma | Predictive of treatment failure after six months: AUC = 0.71; sens.: 65%; spec.: 87%; PPV: 93%; NPV: 54% | Treamtrakanpon et al., 2012 [140] |
| BAFF (↓) (baseline levels <1.5 ng/mL) |
Serum/Plasma | Predictive of clinical (PPV: 87%) and histopathological response (PPV: 83%) (mean follow up: 8.1 months) | Parodis et al., 2015 [135] |
| IL-8 (↓) (baseline levels) |
Serum/Plasma | Lower values predictive of treatment response after 1-year: AUC = 0.64 | Wolf et al., 2016 [141] |
| IL-23 (↓) (baseline levels) |
Serum/Plasma | Predictor for outcome of therapy of induction of remission of active LN: AUC = 0.87 | Dedong et al., 2019 [77] |
| MCP-1 (↑) (baseline levels) |
Urine | Predictive of response to treatment with rituximab at 6 (ORadj = 2.6) and 12 months (ORadj = 0.6) | Davies et al., 2021 [72] |
| Other proteins | |||
| Axl (↑) (baseline levels ≥36.6 ng/mL) |
Serum/Plasma | Predictive of histological response: OR = 5.5; ORadj = 9.3. Decreased levels in responders compared with non-responders after induction therapy. |
Parodis et al., 2019 [131] |
| CD163 (↓) (<370 ng/mmol at month 6) |
Urine | Sens.: 90%; spec.: 87%; PPV: 87%; NPV: 90% to predict a CRR by month 12. | Mejia-Vilet et al., 2020 [101] |
| CSF-1 (↓) (decrease ≥25% after initiation of therapy) |
Serum/Plasma | Predictive of response to therapy and remission: PPV: 88%; NPV: 58% | Menke et al., 2015 [125] |
| HNP1-3 (↓) (baseline levels) |
Serum/Plasma | Predictive of proteinuria remission (mean follow up of 5.5 years): multivariate hazard = 0.2 | Cheng et al., 2015 [142] |
| IL-2Rα (↓) (baseline levels) |
Serum/Plasma | Low levels are predictive of treatment response after 1-year: AUC = 0.63 | Wolf et al., 2016 [141] |
| NGAL (↓) (baseline levels <1964.58 ng/mL) (baseline levels <28.08 ng/mL) |
Urine | Predictive of renal response after 6-month induction therapy: AUC = 0.78; sens.: 81%; spec.: 83%; PPV: 56%; NPV: 95% | Liu et al., 2020 [87] |
| Discrimination between complete/partial response and non-response after 6-month of induction therapy: AUC = 0.77; sens.: 73%; spec.: 68% | Satirapoj et al., 2017 [35] | ||
| NRP-1 (↑) (baseline levels >1143 ng/mg Cr) |
Urine | High baseline levels are predictive of clinical response; AUC = 0.84; sens.: 87%; spec.: 72%; PPV: 88%; NPV: 71% | Torres-Salido et al., 2019 [143] |
| OPG (↓) (baseline levels) |
Serum/Plasma | Low levels are predictive of treatment response after 1-year: AUC = 0.67 | Wolf et al., 2016 [141] |
| RBP4 (↓) (baseline leveles <800 ng/mgCr) |
Urine | Low levels are predictive of proteinuria remission within 12 months of immunosuppressive therapy in active LN patients: AUC = 0.81; sens.: 82%; spec.: 89% | Go et al., 2018 [118] |
| sTNFRII (↑) (baseline levels >8.6 ng/mL) (baseline levels >9.0 ng/mL) |
Serum/Plasma | Predictive of clinical (AUC = 0.86; sens.: 86%; spec.: 80%) and histological response (AUC = 0.90; sens.: 83%; spec.: 80%) among patients with membranous LN (mean follow up: 7.7 months) | Parodis et al., 2017 [83] |
| S100A8/A9 (↑) (baseline levels) |
Serum/Plasma | Differences in disease activity (no response vs. “showing improvement”) in response after 6 months of rituximab: ORadj = 0.3 for both | Davies et al., 2020 [144] |
| S100A12 (↑) (baseline levels) | |||
| TF (↑) (baseline levels) |
Urine | Predictive of response to treatment with rituximab at 12 months (ORadj = 1.4) | Davies et al., 2021 [72] |
| Lymphocytes/immunoglobulins | |||
| IgM (↑) (baseline levels 87.5–402 mg/dL) |
Serum/Plasma | High levels are predictive of CRR at 12 months (OR = 2.1) after immunosuppressive therapy | Ichinose et al., 2018 [137] |
| Lymphocyte count (↑) (baseline levels 1327–2683/μL) |
Serum/Plasma | High levels are predictive of CRR at 12 months (OR = 2.4) after immunosuppressive therapy | Ichinose et al., 2018 [137] |
| MicroRNAs | |||
| miRNA-31-5p (↑) (upregulated at flare time and at month 12) |
Urine | Significantly upregulated in responder group compared to non-responders: flare time: AUC = 0.68; 12 months after treatment: AUC = 0.76 |
Garcia-Vives et al., 2020 [145] |
| miRNA-107 (↑) (upregulated at flare time and at month 12) |
Significantly upregulated in responder group compared to non-responders: flare time: AUC = 0.73; 12 months after treatment: AUC = 0.73 |
||
| miRNA-135b-5p (↑) (upregulated at flare time and at month 12) |
Significantly upregulated in responder group compared to non-responders: flare time: AUC = 0.78; sens.: 78%; spec.: 71%; 12 months after treatment: AUC = 0.86; sens.: 81%; spec.: 79% |
||
| Renal tissue markers | |||
| C9 (+) (positive staining at baseline) |
Kidney biopsy | Positive staining is predictive of poor response at 6 months: OR = 5.4; ORadj = 4.6 | Wang et al., 2018 [138] |
| Podocyte foot process width (↓) (baseline levels 498–897 nm) |
Kidney biopsy | Smaller width is predictive of CRR after induction therapy at 6 months (OR = 4.9) and 12 months (OR = 5.8) after immunosuppressive therapy | Ichinose et al., 2018 [137] |
Biomarkers are structured into subgroups (highlighted in bold) based on clinical/functional affinities. Anti-dsDNA: anti-double-stranded DNA; APRIL: a proliferation-inducing ligand; AUC: area under the curve; BAFF: B-cell-activating factor belonging to the TNF ligand superfamily; CRR: complete renal response; CSF-1: colony stimulating factor 1; C3: complement component 3; C9: complement component 9; HNP1-3: human neutrophil peptide 1-3; HR: hazard ratio; IgM: immunoglobulin M; IL-2Rα: interleukin 2 receptor alpha; LN: lupus nephritis; miRNA: microRNA; MCP-1: monocyte chemoattractant protein 1; NGAL: neutrophil gelatinase associated lipocalin; NPV: negative predictive value; NRP-1: neuropilin 1; OPG: osteoprotegerin; OR: odds ratio; PPV: positive predictive value; RBP4: retinol-binding protein 4; sens.: sensitivity; spec.: specificity; sTNFRII: soluble tumour necrosis factor receptor II; TF: transferrin; uPCR: urine protein to creatinine ratio; ↑: increased; ↓: decreased; (-): negativity; (+): positivity.